Plasma cell tumors in humans most commonly occur as multiple myeloma, an incurable form of cancer. Similar tumors can also be induced in mice by a variety of agents including oils and oncogene containing retroviruses. We have previously demonstrated a number of common features associated with this disease in the two species. These include: 1) a role for T cells in disease progression; 2) an absolute requirement for Interleukin-6 (IL-6) for development of most tumors; 3) bone marrow homing of tumor cells with associated bone destruction. Thus, the murine system appears to be a useful model for both assessing biochemical lesions associated with this form of neoplasia as well as developing new therapeutic approaches. We have recently demonstrated a role for the Insulin-like growth factor receptor I (IGF-IR) signaling pathway in plasma cell neoplasia. IGF-IR was found to be upregulated in both oil and retroviral (raf/myc) induced murine tumors leading to constitutive activation of a downstream signaling cascade involving Insulin response substrate 2 and phosphatidylinositol 3 kinase. This pathway was also constitutively activated in tumors induced by a second retrovirus (abl/myc) and thus deregulated in all plasma cell tumors examined to date. In contrast, deregulation was not observed in a series of B cell tumors and is thus specific to plasma cell disease. The biological relevance of the constitutively activated pathway has been demonstrated both in vitro and in vivo. Recent studies with a series of myeloma lines suggest that the IGF-IR signaling pathway may also be important in the human form of this disease. Six of eight human lines evidence enhanced proliferation in response to IGF-I. An in vivo role for IGF-I was demonstrated by the ability of the OPM-2 line to grow more rapidly in SCID mice when animals received human IGF-I during the period of tumor development. These results indicate that the IGF-I signaling pathway may play an important role in human myeloma, in general, and current studies are aimed at elucidating the downstream signaling elements in this pathway.A second major pathway involved in plasma cell tumor development involves signaling through the IL-6 receptor. IL-6 is absolutely required for development of murine plasma cell tumors and a number of studies in humans similarly suggest an important role in myeloma progression. Studies of the IL-6 pathway have indicated that, immediately downstream of the receptor, Janus kinase 1 (Jak1) plays a critical role in subsequent signaling events. Jak 1 has also been identified as the critical member of this family in IL-4 signaling. We have recently determined that plasma cell tumors lacking Jak1 signal efficiently through both the IL-6 and IL-4 receptors. Furthermore, in lines in which Jak1 is present, phosphorylation (activation) of the protein does not occur in response to either IL-6 or IL-4. Similarly, no other known members of the Janus kinase family have been found to be activated by these cytokines. These results indicate that IL-6 and IL-4 signaling in B lineage cells proceeds through previously unidentified intermediary signaling molecules. Current studies are underway to identify these targets.This project was formerly Z01 BC 05553-28 LG - Cytokines, gene therapy, Oncogenes, Plasma cell tumors, Signal Transduction,